Project Summary. Occipital headaches can be migrainous or non-migraineous. When migrainous, they are often preceded or accompanied by dizziness, vertigo, decreased motor coordination, instability, insecure walking, clumsiness, and reduced coordination ? all of which could be attributed (at least partially) to cerebellar dysfunction ? and muscle tenderness that is aggravated by neck motion. These 2 scenarios suggest that occipital headache can be triggered intracranially, by transient episodes of abnormal cerebellar functioning, and/or extracranially, by acute episodes of neck muscles ache. Given that more than 2/3 of all migraine patients experience muscle tenderness that radiates to the back of the head, it is surprising how little is known about the functional properties of the central neurons that process nociceptive information from the dura overlying the cerebellum, and even more so, how little is known about the mechanisms by which headaches that originate intracranially affect sensory processing of muscles and, vice versa, how tenderness of neck muscles affects processing of sensory signals from the posterior dura. The broad objective of this proposal is to define the neural substrate of occipital headaches. Our working hypothesis is that occipital headaches could be initiated intracranially by cerebellar spreading depression (CbSD) and extracranially by acute muscle pain ? each one involving different patterns of activation and sensitization of C2-4 dorsal horn neurons that innervate posterior dura and neck muscles, and whose axons establish reciprocal connections with brainstem and hypothalamic nuclei that (a) generate some of the classical symptoms of migraine and (b) modulate the firing of these same neurons. This working hypothesis will be tested in 3 aims: 1) determine whether CbSD is capable of activating and/or sensitizing C2-4 dorsal horn neurons that receive convergent signals from the occipital dura and neck muscles; 2) determine whether induction of muscle pain can sensitize these neurons to the extent that it affects how they process sensory signals that originate in the cerebellar dura; and 3) map the axonal course and projection targets of these neurons, and determine whether they receive input from hypothalamic (i.e. orexin, oxytocin), brainstem (i.e., 5HT) and sensory ganglia (i.e. CGRP) neurons thought to play a role in migraine pathophysiology. Clinically, the proposed animal studies have the potential to shed new light on how occipital headaches that begin in pericranial tissues differ from occipital headaches that begin intracranially. Therapeutically, the findings may expand our understanding of cervical manipulations commonly used in the treatment of migraine and non-migraine headaches; from assuming that it is mediated by reduction of nociceptive signals travelling along the occipital nerve to include reduction of nociceptive signals that originate in the posterior dura. Scientifically, the potential to identify novel causes of activation of pain fibers in the posterior dura and the central networks that process such pain can lead to a deeper understanding of the pathophysiology of occipital headache and whether its origin differs from that of frontal/periorbital headache.